Technical Field
The present invention relates to the treatment of motor and non-motor symptoms related to neurodegenerative disorders through pharmacological dermal activation of one or more cranial nerves. In particular the trigeminal, facial, glossopharyngeal, vagus, and hypoglossal, and vestibulocochlear nerves are activated pharmacologically by non-invasive neural signaling to access the regions of the brain and brainstem integral to manifestation of the motor and non-motor symptoms of neurodegenerative conditions.
Background Information
Description of Neurodegenerative Disorders
Neurodegenerative disorders have both motor and non-motor components. Tremor is a typical motor symptom. “Tremor is an unintentional, rhythmic muscle movement involving to and fro movements (oscillations) of one or more parts of the body. It is the most common of all involuntary movements and can affect the hands, fingers, arms, head, face, voice, trunk, and legs. Most tremors occur in the hands.” (National Institute of Neurological Disorders and Stroke 2012). Neurodegenerative disorders that have tremors as a component include Parkinson's disease, essential tremor, Lewy body dementia, multiple sclerosis, frontotemporal dementia, stroke, and traumatic brain injury. Tremors can be differentiated by frequency, amplitude, and when it is exhibited, i.e. resting, postural, or action (kinetic and/or isometric). Tremor differentiation is an important part of disease diagnosis.
Tremor is caused by abnormal changes to brain regions that innervate muscles. There may be multiple causes to these changes, such as disease, trauma, drug or genetic. Here we concern ourselves with neurodegenerative disorders where the symptoms and signs progress over time. Other functions including motor, non-motor, and cognitive, may be affected due to the brain changes and damage.
Parkinson's disease is a progressive and chronic neurodegenerative brain disorder that affects over 1 million people in the United States (FDA 2016). The presence of at least two of the following motor symptoms provides a presumptive diagnosis: resting tremor, bradykinesia (slowed movement), rigidity (dystonia), and postural instability. Other motor and physiological symptoms include kinetic tremor, uncontrolled movement (dyskinesia), restless leg, freezing, impaired balance and coordination, constipation, urinary incontinence and urgency, swallowing difficulty, olfactory dysfunction, weight loss, hypertension, shortness of breath, pain, excessive sweating, cramping and muscle aches. Non-motor symptoms may include cognitive impairment, mood disorders, sleep disturbances, speech difficulties, handwriting problems, visual disturbances, loss of short term or long term memory, impaired comprehension, apathy, impulsivity, depression, anxiety, and fatigue. An area of the brain called substantia nigra has been found to be associated with Parkinson's in progressive loss of neurons that is in turn related to dopamine deficiency (Jellinger, 2002). Lewy bodies consisting of alpha-synuclein are found to accumulate in these neurons.
Lewy body dementia is another example of a neurodegenerative disorder that presents initially with memory impairments, cognitive dysfunction, visual hallucinations, sleep disorders, depression, autonomic dysfunction, repeated falls, hallucinations, and delusions. A major differentiation from Parkinson's is that in LBD motor symptoms appear later than cognitive deficits, whereas in Parkinson's, motor symptoms appear first and cognitive symptoms appear later, and may not be noticeable until 12 months later. It affects approximately 1.4 million people in the U.S. (Lewy Body Dementia Association), is second only to Alzheimer's in dementia. One study showed more pronounced cortical atrophy than Parkinson's disease dementia (Seppi et al., 2007). MRI shows more preservation of the medial temporal lobes and hippocampal structures than with Alzheimer's (Farlow et al., 2016). Lewy bodies are found both inside and outside the substantia nigra, in deep cortical layers throughout the brain, especially in the anterior frontal and temporal lobes, the cingulate gyrus, and the insula. As in Parkinson disease, Lewy bodies in DLB can also be seen in the substantia nigra and locus ceruleus, as well as the raphe nuclei, nucleus basalis of Meynert, and other brainstem nuclei. Neuronal loss in DLB is found in the frontal lobes, nucleus basalis of Meynert, substantia nigra, and locus ceruleus. Synaptic density may also be reduced in the remaining neurons (Imamura et al., 1999).
Essential tremor is the most common tremor disorder affecting about 10 million people in the U.S. Tremor is the main symptom in ET, affecting hands, head, and voice, and possibly legs, trunk, and even internally. Essential tremor can affect all ages. It is believed to be an inherited disorder (International Essential Tremor Foundation 2012). The tremors are usually postural or action (both kinetic and isometric). Non-motor symptoms can include mild cognitive impairment, apathy, depression, anxiety, sleep disturbances. An underlying abnormality of the cerebellum and/or its pathways is the postulate (Benito-Leon et al., 2016).
Multiple sclerosis's common symptoms include sensory symptoms in the limbs or one side of the face, visual loss, acute or subacute motor weakness, diplopia, gait disturbance and balance problems, Lhermitte sign (electric shock like sensations that run down the back and/or limbs upon flexion of the neck), vertigo, bladder problems, limb ataxia, acute transverse myelitis, and pain (Richards R G et al. 2002). Non-motor symptoms may consist of depression, fatigue, and memory impairment. Pathogenesis involves inflammation, demyelination, and axonal degeneration (Dendrou et al., 2015). Lesions are located in the optic nerves, spinal cord, brainstem, cerebellum, and the juxtacortical and periventricular white matter (Popescu et al., 2012). In addition, demyelinated lesions can also be found in the corpus callosum (Barnard et al., 1974) and cortical gray matter (Calabrese et al., 2010; Lucchinetti et al., 2011).
Dystonia comprises various forms that can be differentiated from Parkinson's disease. Tremor is an important clinical feature in dystonia (Pandev et al., 2016). Dystonic tremors can also be differentiated from essential tremor as they occur in conjunction with other dystonic symptoms.
Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that may present with weakness of the extremities or bulbar findings of dysarthria or dysphagia. Both upper motor neurons and lower motor neurons are involved. Death in about 3 years usually is from respiratory difficulties.
Other related movement disorders include ataxia, Huntington's disease, multiple system atrophy, myoclonus, progressive supranuclear palsy, Rhett syndrome, spasticity, and Tourette syndrome.
A major motor function disorder common to all neurodegenerative disorders is dysfunction of ocular gland secretion or ocular surface disease. Symptoms include dryness, grittiness, eye pain, hyperemia, photophobia, blurriness, and excessive tearing. Chronic graft-versus-host-disease is a common occurrence in allogeneic hematopoietic cell transplant. A major neurodegenerative result is mucocutaneous disorder that affects the skin, mouth, liver, lung, eye, and gastrointestinal tract. The manifestations of ocular symptoms resemble those of ocular dysfunction of other neurodegenerative disorders.
Herpes ophthalmicus or shingles, due to either reactivation of varicella-zoster or herpes simplex virus, distributes rash via cranial nerve V trigeminal to the eye and ocular adnexa. Besides painful vesicular rash, ocular symptoms and signs include pain, corneal epithelia defects, decreased corneal sensation, ocular inflammation, eyelid closure problems, and high intraocular pressure. Facial paralysis may also accompany other signs.
Herpes oticus ophthalmicus is the manifestation of the inner, middle, and external ear. There may be severe facial paralysis. Cranial nerve VII facial and VIII vestibulocochlear are involved. Signs and symptoms include painful blisters in and around the ear, the face, mouth and/or tongue, vertigo, nausea, vomiting, hearing loss, tinnitus, eye pain, alterations in taste, inability to close eyelid.
Current Treatment of Motor and Non-motor Related Symptoms
Treatments for motor movement symptoms currently range from systemic pharmacological to electrical stimulation, acupuncture, or surgical or ultrasound thalamotomy. No treatment currently resolves tremor or other motor and non-motor symptoms completely or prevents the disorder or progression. All current treatments are systemic or invasive, and are relatively high dose. Current pharmacological treatments cause many side effects, and many times there is increasing tolerance to dosing, as most of the administered treatments are not aimed specifically at neural targets.
Carbidopa-levodopa (Sinemet, Duopa, Rytary) remains the mainstay of treatment for the signs and symptoms of Parkinson's disease. Other treatments include drugs such as dopamine agonists (Requip-ropinirole, Mirapex-pramipexole, Apokyn-apomorphine, Neupro-rotigotine), COMT (catechol-O-methyltransferase) inhibitors, anticholinergics, and MAO-B (monoamine oxidase type B) inhibitors (Azilect-rasagiline, Deprenyl-selegiline). Deep brain stimulation is also a potential therapeutic option for patients with advanced Parkinson's disease and essential tremor. Non-pharmacological management approaches include exercise, yoga, meditation, diet, and lifestyle modification. Side effects with carbidopa-levodopa may include severe dyskinesia and other symptoms similar to the disease being treated. Reduced efficacy over time has been experienced. Dopamine agonists may be involved with sleep attacks, impulsive behavior, feet swelling,
Surgical and non-invasive thalamotomy has been an alternative for reduction of motor symptoms when medications fail. It is now not a commonly used procedure. It may be used to treat severe tremor on one side of the body (most often in an arm or leg), but does not help with slow movement (bradykinesia), speech problems, or walking difficulties.
Deep brain stimulation (DBS) that involves implantation of an electrical stimulator targeting the subthalamic nucleus (STN) and the globus pallidus interna (GPi), may give significant improvement in dyskinesia in some, but may lead to other issues, such as discomfort with the device, loss of smell and cognitive issues. DBS also carries risks related to electromagnetic interference and debilitation (e.g. inability to speak).
Electrical stimulation has limited efficacy due to many variables, e.g., dose amplitude, pulse rate, and site of location, and does not address the complexity of neural synaptic interactions. It is believed that deep brain stimulation does not restore normal basal ganglia functions, but replaces those that have become abnormal. (Wichmann et al., 2016)
Essential tremor symptoms may be treated with beta blockers (in particular propranolol) or anticonvulsant drugs (in particular primidone). Other beta blockers and anticonvulsants are also used, as well as benzodiazepines, nimodipine, and botulinum toxin. Efficacy declines with time. If medications fail to control symptoms, the condition may also be treated with surgery (thalamotomy) or deep brain stimulation or ultrasound ablation of the thalamus.
Treatments for dystonia are similar to those used for the above tremor related disorders.
Current Lewy body dementia (LBD) treatment is similar to those used for Alzheimer's disease due to the greater cognitive deficit component in LBD. Cholinesterase inhibitors (ravastigmine and donepezil) have had varied success. Memantine and neuroleptics have had limited success.
Current treatments for multiple sclerosis are immune modulating agents that do not address tremor should it exist. Nonmedical options are used when severe tremor is involved.
There is no effective treatment for amyotrophic lateral sclerosis. Riluzole can only prolong survival by a short period.
Antimicrobial agents (e.g., anti-bacterial and anti-viral agents), corticosteroids, intraocular pressure lowering agents, and bandage lenses help to ease the signs and symptoms of herpes ophthalmicus and herpes oticus, but may not address chronic ocular and otic damage and motor symptoms such as facial paralysis.
There is no existing treatment for chronic ocular graft-versus-host disease. Palliative measures do not provide satisfactory relief.
In summary, current treatments for motor and non-motor signs and symptoms of neurodegenerative disorders are either lacking or involve high doses of medications not optimally targeted to the disorder and have undesirable side effects due to lack of specificity toward neural targets, and may even be risky as in the case of electrical deep brain stimulation, ultrasound, or surgical thalamotomy.
The need exists for improved, non-invasive pharmacological treatments for symptoms of neurodegenerative disorders that lack the drawbacks mentioned above.